Molecular mechanism and therapeutic targeting of necrosis, apoptosis, pyroptosis, and autophagy in cardiovascular disease / 中华医学杂志(英文版)

Cell death occurs in various tissues and organs in the body. It is a physiological or pathological process that has different effects. It is of great significance in maintaining the morphological function of cells and clearing abnormal cells. Pyroptosis, apoptosis, and necrosis are all modes of cell death that have been studied extensively by many experts and scholars, including studies on their effects on the liver, kidney, the heart, other organs, and even the whole body. The heart, as the most important organ of the body, should be a particular focus. This review summarizes the mechanisms underlying the various cell death modes and the relationship between the various mechanisms and heart diseases. The current research status for heart therapy is discussed from the perspective of pathogenesis.

Pseudoallergic Reactions of Xuebijing Injection and Its Rational Drug Use / 中国实验方剂学杂志

Objective:To investigate whether the adverse reactions of Xuebijing injection (XBJJ) are mainly pseudoallergic reactions and explore the influencing factors of its pseudoallergic reactions. Method:Mouse model of pseudoallergic reaction was used to study the anaphylactoid reaction of XBJJ which at 0.5, 1 and 2 times of the highest clinical concentration. Next, we compared the differences in pseudoallergic reactions caused by XBJJ for different storage times after preparation. Specifically, XBJJ was prepared into different concentrations, stored for 10 minutes, 2.5 hours, 6 hours and 24 hours, and then injected into the tail vein of mice. Finally, three different injection speeds of 3 seconds, 45 seconds and 90 seconds were selected for XBJJ injection, and then the differences in the paeudoallergic reactions induced by XBJJ in mice under different injection speeds were compared. Result:XBJJ induces pseudoallergic reactions in mice when the drug concentration is higher than the clinically recommended concentration. Compared with storage for 10 minutes after preparation, the degree of pseudoallergic reaction in mice induced by the same concentration of XBJJ increased with the extension of storage time. In addition, when XBJJ was injected in 3 s (the injection rate was 0.083 mL·s^-1), it produced the strongest pseudoallergic reaction. Conclusion:The adverse reactions induced by XBJJ are mainly pseudoallergic reactions. Excessive storage time after preparation and fast injection speed of XBJJ will lead to aggravation of pseudoallergic reactions in mice. When XBJJ is used clinically, it should strictly follow the usage, dosage, concentration, and drip rate recommended in the drug instruction manual. Rational drug use is of positive significance for improving the safety of XBJJ.

Adequate Animal Models of Hyperuricemia for Traditional Chinese Medicine Screening / 中国实验方剂学杂志

Objective:To compare the characteristics of four commonly adopted animal models of hyperuricemia （HUA） for traditional Chinese medicine （TCM） screening， so as to choose the adequate model for screening Chinese herbs and herbal compounds capable of lowering the uric acid. Method:Fifty-four male SD rats were randomly divided into nine groups， namely the normal group， hypoxanthine （HX） + oxonic acid potassium salt （OAPS） model group， yeast extract （YE） + OAPS model group， low-dose adenine （AD） + ethambutol （EMB） model group， high-dose AD + EMB model group， and four positive drug allopurinol （Allo） groups. The modeling lasted for 14 d. The levels of serum uric acid （SUA）， urinary uric acid （UUA）， serum creatinine （SCr）， urea nitrogen （BUN）， kidney injury molecule 1 （KIM-1）， and neutrophil gelatinase-associated lipocalin （NGAL） were detected on the 3rd， 7th， and 14th days. Urine was collected on the 7th and 14th days to investigate changes in urine volume， and the crystals in the residual urine were observed under a polarizing microscope. After the modeling， the kidney was harvested and weighed， followed by pathological examination. Result:The urine volumes in the HX + OAPS model group and high-dose AD + EMB model group were significantly reduced （<italic>P</italic><0.05）. The renal indexes of each model group， except for the YE + OAPS model group， were significantly elevated （<italic>P</italic><0.05， <italic>P</italic><0.01）. The increase in SUA of the HX + OAPS model group and YE + OAPS model group started later （<italic>P</italic><0.05）. The KIM-1 and NGAL levels of the HX + OAPS model group rose significantly from the 7th day （<italic>P</italic><0.05， <italic>P</italic><0.01）， and the BUN increased significantly on the 14th day （<italic>P</italic><0.05）. There was no significant difference in the above-mentioned indicators in the YE + OAPS model group. The SUA levels of the low- and high-dose AD + EMB model groups increased significantly on the 3rd day （<italic>P</italic><0.05， <italic>P</italic><0.01）， with a persistent increase found in the low-dose AD + EMB model group. Besides， the increase in BUN， KIM-1， and NGAL occurred later （<italic>P</italic><0.05， <italic>P</italic><0.01）. By contrast， the high-dose AD + EMB model group exhibited a transient increase in SUA. Moreover， the SCr， BUN， KIM-1， and NGAL elevation occurred earlier and were more obvious than those in the low-dose AD + EMB model group （<italic>P</italic><0.01）. Remarkable histomorphological abnormalities were detected in the kidney of all model groups， except for the YE+OAPS model group， with the most severe injury present in the high-dose AD+EMB model group. Conclusion:The four models commonly used to screen TCM have their own characteristics. In the four models， the SUA elevation in the HX + OAPS model group and YE + OAPS model group started later， with the mild renal injury observed in the HX + OAPS model group instead of the YE + OAPS model group. The SUA of the low-dose AD + EMB model group increased rapidly and lasted for a long time， accompanied by mild renal injury. The SUA of the high-dose AD + EMB model group only showed a transient increase， accompanied by severe renal injury. The investigation on the characteristics and application of different models and the evaluation of these models based on sensitive and objective indicators are helpful for determining the suitable model for the screening of TCM targeting HUA in the future.

Study on synergistic effect of Qingkailing Injection and Shengmai Injection on organ injury in endotoxemia rats / 中国中药杂志

As a dangerous disease with rapid progression, endotoxemia is easy to induce the damage to multiple organs. However, its specific and efficient treatment methods are still lacking at present. Both Qingkailing Injection(QKLI) and Shengmai Injection(SMI) have been proved effective in anti-inflammation, anti-endotoxin and organ protection. In this study, carrageenan and endotoxin were injected successively into rats to establish an endotoxemia model. Different doses of QKLI and SMI were administered to the endotoxemia rats by intraperitoneal injection separately or in combination. Then the count of white blood cells, the number of platelets, the content of cytokines, biochemical indexes, organ coefficient and pathological changes of main organs in the rats were detected. The results showed that the rats in the model group had obvious symptoms of endotoxemia, i.e., leucopenia, thrombocytopenia, increase in cytokines(IL-6 and TNF-α) and biochemical indexes of liver and kidney function as well as pathological damage to liver, kidney and lung. QKLI alone can alleviate the above symptoms of endotoxemia and the organ injury. SMI alone is less effective in improving disseminated intravascular coagulation(DIC) and cytokine secretion complicated with endotoxemia, but capable of reducing the inflammation degree of the lung, liver and kidney. The combination of QKLI and SMI remarkably increased the number of platelets in the peripheral blood, improved the liver and kidney function and reduced inflammatory factors, with lung, liver, kidney and other organ structures protected well. Moreover, the improvement effect of the combination of QKLI and SMI was stronger than those of the two injections alone at fixed doses, indicative of a synergistic effect.

Expression of Cx43 and Cx45 in Cardiomyocytes of an Overworked Rat Model / 法医学杂志

Objective To study the effect of overwork stress response on the expression of connexin 43（Cx43） and connexin 45（Cx45） in cardiomyocytes and on cardiac function. Methods The experimental animals were divided into control group, overworked 1-month group and overworked 2-month group. A overworked rat model was established by forcing swimming of overworked group. The expressions of Cx43 and Cx45 in myocardial tissues of experimental animals were detected by Western blotting, while the corresponding myocardial tissues were stained with hematoxylin-eosin （HE） staining and Masson's staining, then histologically observed. Results Western blotting results showed that, compared with the control group, Cx43 expression in myocardial tissues of overworked rats decreased while Cx45 expression increased. HE staining and Masson's staining results showed that hypertrophy, rupture and interstitial fiber tissue hyperplasia were observed in myocardial fibers of overworked rats. Conclusion Overwork stress response may affect cardiac function as an independent factor and may even cause heart failure or arrhythmias and lead to death.

The Concept, Status Quo and Forensic Pathology of Karoshi / 法医学杂志

"Karoshi" originates from Japan's economic take-off period in the 1960s and 1970s. It is generally believed that overwork lead to the accumulation of fatigue, which triggers the outbreak of potential diseases, and results in sudden death. Karoshi causes great harm to both the community and families because it occurs primarily in 30 to 60 year old young adults. Japan put Karoshi into the category of industrial injury for the first time in 2001 and started to undertake a series of studies in the sociological and pathological fields. However, there is a tremendous gap in the forensic pathological diagnosis domain. In China, research on Karoshi started from the 1990s and is closely related to the reform and opening up policy as well as economic development. According to the incomplete statistics, 600 thousand people die from overwork each year in China, the highest in the world. Karoshi has become one of the most serious social problems in China at the present stage, thus a systematic study in the sociology and forensic pathology fields is urgently required. This paper summarizes the past and present status of Karoshi, and puts forward the problems that need attention during the judicial expertise of Karoshi from forensic pathology perspective.

Mechanism of nephrotoxicity of rhubarb in rats / 中国中药杂志

The aim of this study was to investigate the renal toxicity of rhubarb and its mechanism. The SD rats were randomly divided into three groups: normal group and two rhubarb extract groups (16, 2 g·kg⁻¹). According to the dose conversion method between human and animal, rhubarb 16 g·kg⁻¹ and 2 g·kg⁻¹ were equivalent to 10 times and 1.25 times of human clinical dose respectively. Rhubarb extract was administered by a gastric gavage to rats once daily for 30 days. Serum urea nitrogen （BUN）, creatinine （CRE） and urine KIM-1, NGAL and renal morphology were analyzed. The expressions of OAT1, OAT3 and clusterin mRNA in kidney were measured. The results showed that the low dose of rhubarb had no obvious renal toxicity. The high dose group showed mild and moderate renal injury and a down-regulation of clusterin mRNA expression in the kidney tissue. The renal toxicity in male animals was heavier than that in female animals. There was no significant change in blood BUN and CRE in the high dose group. But urine NGAL level of the high dose group increased by 51.53% compared with normal group, of which male animals increased more significantly (<0.05, compared with the normal group). The expressions of renal OAT1 and OAT3 mRNA in the low dose group were obviously higher than that in the normal group. The results indicated that the high dose of rhubarb could cause the renal toxicity. The dosage should be controlled reasonably in the clinical use. OAT1 and OAT3 mRNA related to anionic transport in kidney tissue played a compensatory protective role in rhubarb-induced renal injury. But the compensatory effect is relatively weak at the high dose level. In addition, routine renal function indicators BUN and CRE had limitation for monitoring the kidney toxicity of rhubarb. It is suggested that urine NGAL detection might be helpful for monitoring the renal toxicity of rhubarb.

Preclinical study on adverse reactions of Xingnaojing injection / 中国中药杂志

In this study, different batches of Xingnaojing injection products were first selected for pseudoallergic mice test, and the results showed that after injection of 6.6-fold clinical dose Xingnaojing injection, the mice showed a slight pseudoallergic reaction, while other mice injected with other batches of injections showed no obvious pseudoallergic reaction. Therefore, it is preliminarily believed that this mice model can effectively indicate the risk of pseudoallergic reactions in the clinical application of Xingnaojing injections. In addition, by changing some of the processes, a high concentration of Xingnaojing injection was prepared for mice pseudoallergic test and guinea pig systemic allergy test. The results showed no significant type Ⅰ allergic reaction in guinea pigs. Mild pseudoallergic reactions occurred in mice after a 6.6-fold clinical dose injection. Therefore, it is considered that for sensitive or idiosyncratic people, the concentration of certain chemical components in Xingnaojing injection will increase after entering the body, which may increase the risk of pseudoallergic reaction. However, due to the limitations of test models, the risk of Xingnaojing injection to induce allergic reactions cannot be ruled out. Finally, by increasing the content of borneol and Tween and (or) sodium chloride in Xingnnaojing Injection and testing its pseudoallergic reactions, the results showed that the combination of these three ingredients may produce new trace sensitization substance and induce pseudoallergic reactions.

Pseudoallergic reaction characteristics of Qingkailing injection and preliminary screening of allergic substances / 中国中药杂志

This study aimed to explore the characteristics and the influencing factors of Qingkailing injection (QKLI) pseudoallergic reaction, and screen out the possible pseudoallergenic substances. The results showed that ICR and Kunming mice had stronger pseudoallergic reactions than BALB/c and C57 mice after being injected with the same dose of QKLI. The pseudoallergic reaction induced by QKLI that was prepared with 0.9% saline was stronger than that prepared with 5% glucose. When the dose was twice of the clinical dose, some batches of QKLI could cause significant or suspected pseudoallergic reactions; when the dose dropped to clinically equal times, all of the batches did not induce pseudoallergic reactions in mice. Different batches of QKLI induced different pseudoallergic reactions in mice. Therefore, QKLI's pseudoallergic reactions might have a certain relationship with different body constitutions. Different solvents might affect the safety of QKLI. QKIL-induced pseudoallergic reactions had the different characteristics between batches, and the dosage should be strictly controlled in clinical use. After the comparison of pseudoallergic reactions induced by different components and different intermediates of QKLI in mice, it was preliminary believed that pseudoallergenic substances might exist in intermediate Isatidis Radix extracts and Gardenia extracts, but specific pseudoallergens shall be furthered studied in subsequent experiences.

Adverse reaction and screening of sensitizing substance of Shuxuening injection / 中国中药杂志

In this study, by the means of the active systemic allergy test in guinea pigs, passive skin allergy test in rats and pseudoallergic test in mice, it was determined that the "allergic reaction" of Shuxuening injection(SXNI) may not be a true IgE-mediated allergic reactions, but mainly of pseudoallergic reaction. Further pseudoallergic test proved that the pseudoallergic reactions of SXNI had difference between batches and showed dose dependence, so it was recommended to establish SXNI pseudoallergic reaction detection method for timely detecting and controlling the product risk of each batch products. In addition, as the pseudoallergic reactions of SXNI were dose-dependent, the dose and concentration of SXNI should be strictly controlled in clinical use. Then the main pseudoallergenic reaction test was conducted for the main monomer components in SXNI and the different fractions of Ginkgo biloba extract in mice, and the results showed that the sensitizing substances may mainly exist in YXY-3 fractions containing flavonol glycosides. By further chemically separating YXY-3, we got four chemical components. Among these four components, YXY-3-1 and YXY-3-2 were testified as the main allergenic components in SXNI through pseudoallergic test in mice. To make sure the specific chemical constituent that is responsible for the pseudoallergic reaction, in-depth study in follow-up experiments should be needed.

Risk control of traditional Chinese medicines containing aristolochis acids (AAs) based on influencing factors of content of AAs / 中国中药杂志

Aristolochic acids (AAs) widely exist in such plants as Aristolochia and Asarum. The renal toxicity of AAs as well as its carcinogenicity to urinary system have been widely known. In 2003 and 2004, China prohibited the use of Aristolochiae Radix, Aristolochiae Manshuriensis Caulis and Aristolochiae Fangchi Radix, and required administering other AAs-containing medicines in accordance with the regulations for prescription drugs. In this paper, we retrieved literatures on the content determination of AAs in recent 10 years in China. It suggested that the AAs content is lower in Asarum herb, especially in its roots and rhizomes, and most of which do not show detectable amount of AA-I. Some of traditional Chinese medicines show fairly small amount of detectable AA-I. The AAs content in Aristolochia herb (including Fructus Aristolochiae, kaempfer dutchmanspipe root) is relatively high; however, there are fewer literatures for studying the content determination of AAs in Chinese patent medicines. There were many factors affecting AAs content, including the parts used, origins, processing methods, extraction process. It suggested that we should pay attention to the toxicity of Chinese medicines containing AAs and use these decoction pieces and traditional Chinese medicines cautiously. In addition, basic studies for the origins, processing methods and extraction process of Chinese patent medicines containing AAs, as well as supervision and detection of AAs content in traditional Chinese medicinal materials, decoction pieces and Chinese patent medicines shall be strengthened for reducing medication risk and guaranteeing clinical medication safety.

Preclinical evaluation of pseudoallergic reactions on Chinese herbal injections: study on animal strain and gender difference / 中国中药杂志

Pseudoallergic reactions occured after the first administration of patients, and the pathogenic mechanisms of them were different from the allergic reactions which needed excitation after antigen sensitization. To provide a basis for evaluation, clinical use and drug development of pseudoallergic reactions, the models were established by two kinds of Chinese herbal injections (CHI) both on different strain or gender mice. With the use of ICR, Kunming, BALB/C, C57 mice, pseudoallergic tests of two CHI were conducted to compare the sensitivity of four strains mice, and compared the differences in male and female animals. Test substances contain 0.8% Evans blue (EB) were intravenously injected into different strain and gender mice. Scores of ear blue staining and quantitation of ear EB exudation were the parameters for pseudoallergic reaction. Results of strain difference indicated that both CHI A and B could cause severe pseudoallergic reactions indicated by obvious vascular hyperpermeability on ICR mice. The pseudoallergic reactions in ICR mice are more obvious under the the same dose of injection, which stated the sensibility of ICR mice. And the reactions of KM mice and BALB/C mice were slightly reduced which compared to ICR mice, even alomost nothing on C57 mice. Comparison results of gender difference showed that one CHI was not have significant difference in male and female animals, but male animals were more susceptible than females on another CHI. Therefore, ICR mice were preferable experimental strain on the model of pseudoallergic reactions induced by CHI A and B. Because of female animals were easily influenced by estrous cycle, the pseudoallergic reactions induced by CHI A and B select and use male mice befittingly.

Prognosis of the short-term efficacy of thymectomy for myasthenia gravis with serum protein profiles / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>The extended thymectomy for myasthenia gravis (MG) is currently available, but in 20% - 40% of the patients the results were not satisfactory. There are no ideal indicators forecasting surgical results before operation. The surface enhanced laser desorption ionization-time of flight-mass spectroscopy (SELDI-TOF-MS) is a currently new technique for detection of protein profiles, and some progresses have been made in cancer diagnosis and efficacy evaluation, but there is no report on efficacy forecasting of MG surgery. This study aimed to establish an efficacy prognosis model for forecasting the efficacy of surgery for MG by analysis of serum protein profiles of MG patients before surgery.</p><p><b>METHODS</b>Fifty-six MG patients 6 months after extended thymectomy were enrolled in the study. They were classified into effective or non-effective groups according to symptoms and medication. Their pre-operative blood samples were analyzed for protein profiles by the SELDI-TOF MS technique, and protein peaks were identified for establishment of the efficacy prognosis model of MG surgery. Additional 100 MG patients were subjected to model validation and their pre-operation protein profiles reviewed for post-operative results. The results were compared with those of the post-operative follow-up so as to validate the prognosis model.</p><p><b>RESULTS</b>For the model establishment, symptoms were improved in 33 patients and not improved in 18 patients, with an effective rate of 64.7%. Five (8.9%) patients were lost to follow-up. Within the molecular weight range of 1 000 to 20 000, 3 specific protein peaks were found to be significantly different between the effective and non-effective groups, ie M4110-76, M3394-58, and M1258-55. Using the efficacy prognosis model constructed with these data, the accuracy rate of classification was 87.9% for the effective group, and 83.3% for the non-effective group, with a total accuracy rate of 86.3%. For the model evaluation, 2 (8.9%) patients were lost to follow-up, 62 patients were effective and 36 were non- effective. By comparing with the real results of follow-up with 65 effective and 33 non-effective patients with an effective rate of 66.3%, the accuracy rate of prediction by the prognosis model was 86.2% for the effective group, and was 81.8% for the non-effective group with a total accuracy rate of 84.5%.</p><p><b>CONCLUSIONS</b>By protein profiles analysis of pre-operative blood samples taken from MG patients with the SELDI-TOF MS technique, protein peaks correlated with surgery efficacy in MG patients can be found for primary forecasting short-term efficacy of surgery for MG patients.</p>

Clinical observation of cut healing with gelatin paste after cervical intraepithelial neoplasia surgery by LEEP / 中国基层医药

Objective To observe the poet-operative clinical inpact on cervical intraepithelial neoplasia surgery by Loop elcctrosurgical excision procedure(LEEP),gelatin paste to improve the healing of the Cut,prevent the post-operative bleeding,and find out effective methods of preventing LEEP complications.Methods 100 patients with cervical intraepithelial neoplasia underwent LEEP in clinic.Divide them into two groups randomly,60 patients were adopted gelatin paste post-LEEP ag the cure group.while 40 patients were adopted as control group.Observation Vaginal bleeding,infection and cervical rear in short-term.Results In 60 patients of cure group,never patients with vaginal bleeding,infection and the cut healing in the short time.In 40 patients of control group,three patients with vaginal bleeding,two patients with infection,and three patients with bad healing.The different between two group with vaginal bleeding,infection and the cut healing time was significant(P＜0.05).Condusion gelatin paste can reduce bleeding.infection and cervical repair bad cmpllcations after cervical intraepithelial neoplasia surgery by LEEP.

The evaluation of thrombotest on patients suffering from perioperative hemorrhage / 中国普通外科杂志

1000 ml).Methods From 2000 to 2002,a total of 89 critically ill surgical patients were enrolled whose preoperative liver function and blood analysis were normal. The patients′ heart rate?blood pressure?body temperature?hemoglobin(Hb)?platelet count(PLT)?hematocrit(HCT)?prothrombin time(PT)?activated partial thrombo-plastin time(APTT)?fibrinogen concentration(FIB)?fibrinogen degrade product(FDP)?D-dimer immediately after enrollment into the study were determined. Results As the blood loss increased PT prolonged from(11.4?0.6) s to (16.0?0.6) s ( P